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Brain Advance Access originally published online on January 19, 2005
Brain 2005 128(3):659-670; doi:10.1093/brain/awh381
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please e-mail: journal.permissions{at}oupjournals.org

Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients

Hiroaki Adachi1, Masahisa Katsuno1, Makoto Minamiyama1, Masahiro Waza1, Chen Sang1, Yuji Nakagomi2, Yasushi Kobayashi1, Fumiaki Tanaka1, Manabu Doyu1, Akira Inukai1, Mari Yoshida3, Yoshio Hashizume3 and Gen Sobue1

1 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, 2 Central Research Laboratories, School of Medicine, Aichi Medical University and 3 Department of Neuropathology, Institute for Medical Sciences of Aging, Aichi Medical University of Aichi, Japan

Correspondence to: Gen Sobue, MD, PhD, Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, 466-8550, Japan E-mail: sobueg{at}med.nagoya-u.ac.jp

Spinal and bulbar muscular atrophy (SBMA) is an inherited adult onset motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor (AR), affecting only males. The characteristic pathological finding is nuclear inclusions (NIs) consisting of mutant AR with an expanded polyQ in residual motor neurons, and in certain visceral organs. We immunohistochemically examined 11 SBMA patients at autopsy with 1C2, an antibody that specifically recognizes expanded polyQ. Our study demonstrated that diffuse nuclear accumulation of mutant AR was far more frequent and extensive than NIs being distributed in a wide array of CNS nuclei, and in more visceral organs than thus far believed. Mutant AR accumulation was also present in the cytoplasm, particularly in the Golgi apparatus; nuclear or cytoplasmic predominance of accumulation was tissue specific. Furthermore, the extent of diffuse nuclear accumulation of mutant AR in motor and sensory neurons of the spinal cord was closely related to CAG repeat length. Thus, diffuse nuclear accumulation of mutant AR apparently is a cardinal pathogenetic process underlying neurological manifestations, as in SBMA transgenic mice, while cytoplasmic accumulation may also contribute to SBMA pathophysiology.


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